The ultimate goal of this proposal is to gain insight into the mechanisms of immunity, inflammation and tissue injury in the host response to cutaneous infection. Leprosy provides a model for studying the interaction between the systemic and local immune responses in skin, because its diverse clinical manifestations correlate with the host immune response to the pathogen, Mycobacterium leprae. In the tuberculoid (T-lep) form of disease, the infection is self-healing, with few bacteria in few skin lesions, while in the lepromatous (L-lep) form, the infection is progressive, with high bacterial loads in disseminated skin lesions. Furthermore, patients develop immunologic reactions, permitting the study of acute inflammation over time. We have elected to focus on the Th17 and recently identified Th22 cells and their role in leprosy, given our exciting preliminary data linking Th17 cells at the site of disease in the self-limited form of leprosy, tuberculoid (T-lep) and Th22 cells to the acute inflammatory reactional state, erythema nodosum leprosum (ENL). These findings form the basis for our central hypothesis that Th17 cells contribute to host defense in response to microbial infection in skin, whereas in contrast, Th22 cells contribute to acute inflammation and immune-mediated tissue injury. The revised specific aims are to investigate: 1) the mechanisms by which the innate immune system recognizes M. leprae and triggers the induction of Th17 vs. Th22 cells, 2) the mechanisms by which Th17 and Th22 cells contribute to host defense, and, 3) the mechanisms inducing Th17 and Th22 to trigger neutrophil recruitment, a key factor in acute inflammation and immune-mediated tissue injury. By studying the differential role of Th17 and Th22 cells in skin lesions from across the spectrum of leprosy as model, we hope to target an integrated understanding by which the innate immune response influences the adaptive response with relevance to host defense and tissue injury in the context of microbial infection in humans, and, we would hope, would provide the ability to predict disease outcome and also lead to the development of new immunomodulatory treatments for a variety of infectious and skin diseases. PUBLIC HEALTH RELEVANCE: Leprosy continues as a major health and economic burden in developing countries and also provides an extraordinary model to study human immune responses to a microbial pathogen because it is a skin disease, such that the lesions are readily accessible for study of immune processes at the site of disease. Our preliminary data demonstrate unique insights into human immune responses from the study of leprosy, including the biologic/immunologic pathways that contribute to resistance vs. susceptibility to progressive infection. The investigation of these aspects of host defense mechanisms will yield new insights into the human immune system as well as provide novel targets for therapeutic intervention against a variety of infectious and skin diseases.